Total pancreatectomy and islet autotransplantation (TP-IAT) are currently being performed to treat intractable pain in selected patients with chronic pancreatitis (CP). Our center at the Medical University of South Carolina (MUSC) has undertaken more than 100 cases of TP-IAT since 2009, with the expectation of an increasing patient volume based on our current patient pool. A major hurdle in this procedure is that less than 30% of patients become insulin-independent after TP-IAT, compared to the >85% diabetes-free rate before surgery. A dramatic islet cell death during harvest and post-transplantation compromised their function. Currently, no interventional protocols are in place with the goal to increase the survival of islet autograft in TP-IAT patients. Thus, effective therapies that can facilitate islet cell engraftment and promote survival after transplantation are not only urgently needed for the prevention of post-surgical diabetes after TP-IAT in CP patients, but can potentially serve as a platform on which to address the more complex allogeneic islet cell transplantation for patients with type 1 diabetes. An ever-increasing body of literature demonstrates that transplantation of islets together with mesenchymal stem cells (MSCs) enhances islet engraftment, decreases number of islets needed to achieve normoglycemia by promoting function and regeneration of cells and by modulating function of T cells in the mouse and nonhuman primates islet allogeneic transplantation models. The fact that MSCs can proliferate ex vivo and can migrate to the site of injury, including the liver where the islets are transplanted when injected intravenously in vivo, make them an ideal synergistic treatment option for islet autotransplantation. MSCs are currently being tested in more than 20 clinical trials for the treatment of type 1 and type 2 diabetes and their associated complications based on their remarkable immunoregulatory and regenerative properties. We have found that co-culturing mouse islets with syngeneic MSCs rescued them from hypoxia-induced apoptosis and enhanced their glucose response. However, the protective effects of MSCs during TP-IAT in CP patients has yet to be evaluated and will be the focus of this grant. Based on current data from others and our group, we hypothesize that co-transplantation of islets with autologous MSCs expanded ex vivo, can enhance islet engraftment after transplantation resulting in more CP patients being diabetes free after TP-IAT. In this study, we will harvest MSCs from CP patients, characterize their phenotype, confirm their protective effects in islets, and set up the standard protocol to harvest cells to clinical grade. We will then carry out a pilot/feasibility stdy in a group of patients to evaluate whether patients receiving islets together with autologous MSCs have a better chance of being insulin-independent after IAT. Based on our active islet transplantation program at MUSC, this treatment procedure can be readily translated into therapy to benefit patient care.